Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS

Cho Mar Myint Wai; Shangying Chen; The Phyu; Shuangyi Fan; Sai Mun Leong; Wenning Zheng; Louis Ching Yi Low; Shoa Nian Choo; Chi Kuen Lee; Tae Hoon Chung; Kenneth Hon Kim Ban; Soumita Ghosh; Stefanus Lie; Seiichi Kato; Shigeo Nakamura; Emiko Takahashi; Young Hyeh Ko; Joseph D. Khoury; Shih Sung Chuang; Rex K.H. Au-Yeung; Soo Yong Tan; Soon Thye Lim; Choon Kiat Ong; Yong Howe Ho; Li Mei Poon; Sanjay De Mel; Anand D. Jeyasekharan; Wee Joo Chng; Franziska Otto; Leticia Quintanilla-Martinez; Federica Zanardi; Fabio Iannelli; Claudio Tripodo; Jason J. Pitt; Siok Bian Ng

doi:10.3324/haematol.2021.280003

Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS

Cho Mar Myint Wai, Shangying Chen, The Phyu, Shuangyi Fan, Sai Mun Leong, Wenning Zheng, Louis Ching Yi Low, Shoa Nian Choo, Chi Kuen Lee, Tae Hoon Chung, Kenneth Hon Kim Ban, Soumita Ghosh, Stefanus Lie, Seiichi Kato, Shigeo Nakamura, Emiko Takahashi, Young Hyeh Ko, Joseph D. Khoury, Shih Sung Chuang, Rex K.H. Au-YeungSoo Yong Tan, Soon Thye Lim, Choon Kiat Ong, Yong Howe Ho, Li Mei Poon, Sanjay De Mel, Anand D. Jeyasekharan, Wee Joo Chng, Franziska Otto, Leticia Quintanilla-Martinez, Federica Zanardi, Fabio Iannelli, Claudio Tripodo, Jason J. Pitt, Siok Bian Ng

Hematopathology

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copy-number aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCL-EBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

Original language	English (US)
Pages (from-to)	1864-1879
Number of pages	16
Journal	Haematologica
Volume	107
Issue number	8
DOIs	https://doi.org/10.3324/haematol.2021.280003
State	Published - Aug 2022

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Hematology

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10.3324/haematol.2021.280003

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Wai, C. M. M., Chen, S., Phyu, T., Fan, S., Leong, S. M., Zheng, W., Low, L. C. Y., Choo, S. N., Lee, C. K., Chung, T. H., Ban, K. H. K., Ghosh, S., Lie, S., Kato, S., Nakamura, S., Takahashi, E., Ko, Y. H., Khoury, J. D., Chuang, S. S., ... Ng, S. B. (2022). Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS. Haematologica, 107(8), 1864-1879. https://doi.org/10.3324/haematol.2021.280003

Wai, CMM, Chen, S, Phyu, T, Fan, S, Leong, SM, Zheng, W, Low, LCY, Choo, SN, Lee, CK, Chung, TH, Ban, KHK, Ghosh, S, Lie, S, Kato, S, Nakamura, S, Takahashi, E, Ko, YH, Khoury, JD, Chuang, SS, Au-Yeung, RKH, Tan, SY, Lim, ST, Ong, CK, Ho, YH, Poon, LM, De Mel, S, Jeyasekharan, AD, Chng, WJ, Otto, F, Quintanilla-Martinez, L, Zanardi, F, Iannelli, F, Tripodo, C, Pitt, JJ & Ng, SB 2022, 'Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS', Haematologica, vol. 107, no. 8, pp. 1864-1879. https://doi.org/10.3324/haematol.2021.280003

@article{5965c1649ce7486194f0e978d9a804f4,

title = "Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS",

abstract = "Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copy-number aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCL-EBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.",

author = "Wai, {Cho Mar Myint} and Shangying Chen and The Phyu and Shuangyi Fan and Leong, {Sai Mun} and Wenning Zheng and Low, {Louis Ching Yi} and Choo, {Shoa Nian} and Lee, {Chi Kuen} and Chung, {Tae Hoon} and Ban, {Kenneth Hon Kim} and Soumita Ghosh and Stefanus Lie and Seiichi Kato and Shigeo Nakamura and Emiko Takahashi and Ko, {Young Hyeh} and Khoury, {Joseph D.} and Chuang, {Shih Sung} and Au-Yeung, {Rex K.H.} and Tan, {Soo Yong} and Lim, {Soon Thye} and Ong, {Choon Kiat} and Ho, {Yong Howe} and Poon, {Li Mei} and {De Mel}, Sanjay and Jeyasekharan, {Anand D.} and Chng, {Wee Joo} and Franziska Otto and Leticia Quintanilla-Martinez and Federica Zanardi and Fabio Iannelli and Claudio Tripodo and Pitt, {Jason J.} and Ng, {Siok Bian}",

year = "2022",

month = aug,

doi = "10.3324/haematol.2021.280003",

language = "English (US)",

volume = "107",

pages = "1864--1879",

journal = "Haematologica",

issn = "0390-6078",

publisher = "Ferrata Storti Foundation",

number = "8",

}

TY - JOUR

T1 - Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS

AU - Wai, Cho Mar Myint

AU - Chen, Shangying

AU - Phyu, The

AU - Fan, Shuangyi

AU - Leong, Sai Mun

AU - Zheng, Wenning

AU - Low, Louis Ching Yi

AU - Choo, Shoa Nian

AU - Lee, Chi Kuen

AU - Chung, Tae Hoon

AU - Ban, Kenneth Hon Kim

AU - Ghosh, Soumita

AU - Lie, Stefanus

AU - Kato, Seiichi

AU - Nakamura, Shigeo

AU - Takahashi, Emiko

AU - Ko, Young Hyeh

AU - Khoury, Joseph D.

AU - Chuang, Shih Sung

AU - Au-Yeung, Rex K.H.

AU - Tan, Soo Yong

AU - Lim, Soon Thye

AU - Ong, Choon Kiat

AU - Ho, Yong Howe

AU - Poon, Li Mei

AU - De Mel, Sanjay

AU - Jeyasekharan, Anand D.

AU - Chng, Wee Joo

AU - Otto, Franziska

AU - Quintanilla-Martinez, Leticia

AU - Zanardi, Federica

AU - Iannelli, Fabio

AU - Tripodo, Claudio

AU - Pitt, Jason J.

AU - Ng, Siok Bian

PY - 2022/8

Y1 - 2022/8

N2 - Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copy-number aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCL-EBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

AB - Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copy-number aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCL-EBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

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JO - Haematologica

JF - Haematologica

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ER -

Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS

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